Marker Of Tumor Response Research Articles

Analysis of metabolic response (MR) by positron emission tomography (PET) compared with tumor response by computed tomography (CT) from MPACT, a phase III trial comparing nab-paclitaxel (nab-P) plus gemcitabine (G) versus G alone for patients (pts) with metastatic adenocarcinoma of the pancreas.

254^ Background: In the MPACT trial, nab-P + G demonstrated superior efficacy vs G alone for the treatment of metastatic pancreatic cancer (PC). Pts with an MR (according to EORTC criteria) had a 5-month improvement in median overall survival (OS) vs those without an MR (13 vs 8 months for nab-P + G and 12 vs 7 months for G alone). This analysis examines the relationship between MR by PET and tumor response by CT. Methods: Previously untreated pts (N = 861) with metastatic PC were randomized 1:1 to receive nab-P 125 mg/m2 + G 1000 mg/m2 on days 1, 8, and 15 every 4 wk or G alone 1000 mg/m2 weekly for 7 wk followed by 1 wk of rest (cycle 1) and then days 1, 8, and 15 every 4 wk (cycle ≥ 2). Tumor responses were evaluated every 8 wk by CT using RECIST v1.0. CT-documented disease progression led to treatment discontinuation. PET scans were evaluated at baseline, wk 8, and wk 16. Results: In 257 pts with a PET scan at baseline, 252 (98%) had ≥ 2 PET-avid lesions. The rate of MR (complete [CMR] or partial [PMR]) was higher for nab-P + G vs G alone (63% vs 38%; P < 0.0001). The ORRs by CT (complete response + partial response [CR/PR]) in the same pts were 31% for nab-P + G vs 11% for G. In a pooled-treatment-arm analysis (n = 255), 130 pts (51%) had an MR by PET, and 54 (21%) had a CR or PR by CT. Among pts with an MR by PET, 32% had a CR or PR, 43% had stable disease, and 16% had progressive disease (PD) by CT. Pts who had an MR by PET in the absence of a CR or PR by CT (n = 88) had a median OS of 10 months (table). Conclusions: Rates of MR by PET in this trial were > 2-fold the response rates by CT, suggesting that PET may be a more sensitive marker of tumor response. Of the pts without a CR or PR by CT, those with an MR by PET had a longer median OS vs those without one. A set of pts who had PD by CT exhibited an MR by PET. Thus, PET may identify a set of pts who may benefit from continued treatment despite PD by CT. Further research is needed to explore the radiological and clinical characteristics of these pts. Clinical trial information: NCT00844649. [Table: see text]

Evaluation of Non-Invasive Multispectral Imaging as a Tool for Measuring the Effect of Systemic Therapy in Kaposi Sarcoma

Diffuse multi-spectral imaging has been evaluated as a potential non-invasive marker of tumor response. Multi-spectral images of Kaposi sarcoma skin lesions were taken over the course of treatment, and blood volume and oxygenation concentration maps were obtained through principal component analysis (PCA) of the data. These images were compared with clinical and pathological responses determined by conventional means. We demonstrate that cutaneous lesions have increased blood volume concentration and that changes in this parameter are a reliable indicator of treatment efficacy, differentiating responders and non-responders. Blood volume decreased by at least 20% in all lesions that responded by clinical criteria and increased in the two lesions that did not respond clinically. Responses as assessed by multi-spectral imaging also generally correlated with overall patient clinical response assessment, were often detectable earlier in the course of therapy, and are less subject to observer variability than conventional clinical assessment. Tissue oxygenation was more variable, with lesions often showing decreased oxygenation in the center surrounded by a zone of increased oxygenation. This technique could potentially be a clinically useful supplement to existing response assessment in KS, providing an early, quantitative, and non-invasive marker of treatment effect.

Abstract P4-04-15: UC San Diego molecular tumor board: Experience in breast cancer

Abstract Background: To realize the promise of personalized medicine, it is important to build the infrastructure to match patients to the most promising therapies using evolving genomic information to inform clinical trial and treatment recommendations. Methods: A molecular tumor board was established in December 2012 consisting of representatives of medical oncology, surgery, radiation, pathology, radiology, clinical genetics, molecular genetics and diagnostics, basic and translational science, and bioinformatics and pathway analysis. Patients with metastatic breast cancer signed consent for collection of data in a registry format related to clinical history, genomic analysis, treatment recommendations, and response. Tumor specimens from patients with metastatic breast cancer were subjected to a next generation sequencing diagnostic test (Foundation One™) in a CLIA-certified lab (Foundation Medicine) and analyzed for genomic alterations in a 182 gene panel or a 236 gene panel. Clinical cases and genomic alterations were discussed at Molecular Tumor Board where clinical trials and treatment recommendations were considered, with the final decision made by the treating oncologist. Results: Genomic analyses of metastatic breast cancer specimens from 17 consented patients had at least one genomic alteration and no tumors had the same genomic alterations. 12/17 had ≥ 2 and 4/17 had 6 or 7 genomic alterations. The most common genomic alterations were in PIK3CA observed in tumors from 6/17 patients. 1/17 tumor specimens had only a single genomic alteration for which there are no current targeted drugs in clinical studies or available commercially (GATA3). Radiographic and/or tumor marker response have been observed to date in 3/4 heavily pretreated patients following treatment with a targeted therapy or a targeted therapy informed by the genomic data in combination with other drugs. Conclusions: The strategy of matching targeted clinical trial and commercially available therapies to genomic alterations of tumor specimens from individual patients with metastatic breast cancer may offer promise to patients with advanced refractory disease. Biopsies of metastatic disease, genomic analysis in CLIA labs, establishment of molecular tumor boards, definition of “matched” versus “non-matched” therapies, capturing data in a registry to create a learning environment, and most importantly, availability of targeted therapies in clinical trials or commercially, are required for this individual patient strategy to inform current and future treatment options for much larger patient populations. Funding from UC San Diego Moores Cancer Center MyAnswerToCancer philanthropic fund. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-04-15.

Excellent Response to Combined Radioiodine and Enoxaparin in the Setting of Tumor Venous Thrombosis from Differentiated Thyroid Carcinoma Involving Internal Jugular and Subclavian Veins

A striking clinical, radiological and tumor marker response obtained with a combined approach of radioiodine (I-131; single fraction) coupled with subcutaneous enoxaparin (a low-molecular-weight heparin) in the setting of differentiated thyroid carcinoma with jugular vein tumor thrombosis and metastatic pulmonary disease is described in this article. Pulmonary metastases, a frequent accompaniment in this group of patients, also demonstrated remarkable response with a single fraction of I-131. The proposed approach of combining targeted I-131 therapy with the antithrombotic effect of low-molecular-weight heparin in patients with thyroid cancer with documented tumor venous thrombosis is likely to produce a synergistic effect, with a dramatic clinical response that requires a minimal I-131 dose. The noninvasive nature and ease of the approach, which has an impressive response and findings, calls for administering this therapeutic option more in such patients in the future. This could lead to the development of an effective treatment strategy in these patients based upon generated evidence.

Abstract B231: Jab1/Csn5 a new player driving the resistance to Her2-targeted therapies for breast cancer.

Abstract Her2 a key member in the epidermal growth factor receptor (EGFR) family, is one of the most dominant oncogenes in breast cancer. It is overexpressed in approximately 25%-30% of human breast cancers, which confers a more aggressive tumor phenotype and is associated with poor prognosis. The most effective FDA-approved therapy targeting Her2 is the monoclonal antibody trastuzumab (Ttzm; Herceptin). Ttzm inhibits Her2 activation and blocks downregulation of PI3K/Akt activities, which ultimately leads to increased expression of the cyclin-dependent kinase inhibitor p27, cell cycle arrest, and/or apoptosis. However, about 75% of Her2-positive breast tumors are or become resistant to Ttzm and experience relapse or disease progression. This suggests that tumors acquire or possess an intrinsic mechanism of resistance that prevents from Her2 inhibition. Therefore, it is important for the clinic to identify novel pathway to overcome the resistance. Clinicians cannot predict which patients with Her2-positive breast cancer will benefit from this treatment. Despite extensive studies, the mechanisms and genes responsible for resistance to trastuzumab (Ttzm) have not been entirely identified. Thus, novel strategies for treating Her2-positive disease are urgently needed. Recent studies have proposed that resistance to Ttzm is related to IGF-1R overexpression, rapid p27 degradation, PTEN loss, and PI3K mutations, but a clear target for modifying its resistance has yet to be identified. The cytostatic effect of Ttzm correlates with downregulation of Akt activity, which ultimately leads to increased expression of the cyclin-dependent kinase inhibitor p27, cell cycle arrest and/or apoptosis. c-Jun activation domain-binding protein 1 (Jab1/Csn5), a novel candidate oncogene that we identified, contributes to the progression of breast carcinoma and is correlated with poor prognosis. Jab1/Csn5 expression is low or absent in normal adults breast tissues, but over-expressed in 50% of primary breast tumor and 90% of metastatic breast cancer and other tumor types (ovarian cancer, pancreatic, non-small-cell lung carcinoma, and non-Hodgkin's lymphomas). Jab1/Csn5 negatively regulates p27 tumor suppressor gene, mediates p27 nuclear-to-cytoplasmic export and degradation. Jab1 levels are inversely associated with p27 expression in vitro and in vivo, which means that its up-regulation may contribute to trastuzumab (Ttzm) resistance by promoting p27 degradation. This study was conducted to investigate the role of Jab1 in modulating trastuzumab (Ttzm) resistance. We hypothesize that overexpression of Jab1 plays a crucial role in resistance to Ttzm through negative regulation of the cell-cycle inhibitor p27. Using molecular approaches and pre-clinical studies we identified the pathway leading to resistance the Ttzm. In this study, we will test a novel paradigm that inhibition of Jab1 expression renders Ttzm-resistant cells sensitive to Ttzm by stabilizing nuclear p27 expression levels. Finally Jab1 could be used as a predictive marker of tumor response to Ttzm, which could assist clinicians in selecting the best treatment modalities for patients with breast cancer Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B231. Citation Format: Thuy T. Vu, Terry J. Shackleford, Qingxiu Zhang, Francisco J. Esteva, Elias Drakos, Ling Tian, Timothy Kute, Aysegul A. Sahin, George Z. Rassidakis, Francois X. Claret. Jab1/Csn5 a new player driving the resistance to Her2-targeted therapies for breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B231.

Abstract A2: Exploratory textural CT evaluation of the combination of TRC105 (anti-endoglin monoclonal antibody; MAb) and bevacizumab (BEV) indicates partial response by Choi criteria in BEV refractory advanced cancer patients (pts) and identifies candidate markers of response.

Abstract Background: Endoglin (CD105) is an endothelial cell membrane receptor, highly expressed on angiogenic tumor vessels, that is essential for angiogenesis and upregulated by hypoxia and VEGF inhibition. TRC105 is an anti-endoglin MAb that potentiates VEGF inhibitors in preclinical models. TRC105 10 mg/kg weekly was well tolerated with BEV 10 mg/kg q2wk and the combination demonstrated activity in BEV and VEGF TKI refractory pts. This study assessed radiographic responses to TRC105 + BEV using Choi criteria and tumor morphology by applying novel quantitative textural analysis (QTA: TexRad -University of Sussex, UK) in pts with durable stable disease by RECIST, to determine predictive markers of response. Methods: Contrast enhanced CT scans from 5 pts with advanced solid tumors who demonstrated stable disease by RECIST in a trial of escalating doses of TRC105 (3, 6, 8 or 10 mg/kg/wk) plus BEV were reviewed. Seventeen target lesions were selected from baseline scans and assessed for target lesion diameter, whole lesion density, and tumor volume at baseline and follow-up. QTA analysis was assessed on the same target lesions using six different filter levels at baseline and on follow-up scans. The results were correlated to anatomic tumor response using non-parametric evaluation and regression analysis. Statistical significance was defined as a two-tailed p < 0.05. Results: Scans from 5 patients (median age 56; M:F 2:3; median 4 prior regimens; 3 metastatic colorectal and 2 ovarian cancer) 4 of whom progressed following VEGF inhibitor treatment were selected and demonstrated stable disease by RECIST for at least 4 months (range: 4-14 months) of treatment with TRC105 + BEV. Four of five patients (80%) had partial responses by Choi criteria. Predictive markers of tumor response on baseline scans included 1) elevated mean pixel density (median values of responder (R) vs non responder (NR): 27.2 vs -4.3) that correlated with subsequent tumor size reduction, 2) elevated entropy (a measure of tumor heterogeneity; median R vs NR: 5.1 vs 4.7) that correlated with subsequent decrease in mean tumor volume, and 3) low kurtosis (a measure of tumor heterogeneity; median R vs NR: 0.2 vs 1.1) that correlated with subsequent reduction in lesion density (p<0.01). Mean positive pixel values (an indicator of hypoxia) on follow-up scans correlated with decreased tumor density. Conclusions: Assessment of radiographic response using Choi criteria identified VEGF inhibitor refractory patients who demonstrated partial response to the combination of TRC105 + BEV. Using novel QTA measures, markers of tumor heterogeneity and hypoxia correlated with individual lesion responses and are worthy of prospective evaluation as predictive imaging biomarkers. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A2. Citation Format: Ron L. Korn, Michael S. Gordon, Lee S. Rosen, Francisco Robert, Daniela Matei, Jonathan W. Goldman, David S. Mendelson, E. Gabriela Chiorean, Robert Matthew Strother, Ben K. Seon, Delia Alvarez, Bonne J. Adams, Charles P. Theuer. Exploratory textural CT evaluation of the combination of TRC105 (anti-endoglin monoclonal antibody; MAb) and bevacizumab (BEV) indicates partial response by Choi criteria in BEV refractory advanced cancer patients (pts) and identifies candidate markers of response. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A2.

Sorafenib in metastatic radioactive iodine-refractory differentiated thyroid cancer: A pilot study

The incidence and mortality of thyroid cancer are on the increase worldwide and the treatment options for progressive, radioactive iodine (RAI)-refractory metastatic differentiated thyroid cancer (DTC) patients are currently limited. Sorafenib is a multikinase inhibitor that targets several molecular signals, which are believed to be involved in the pathogenesis of DTC. In this study, we reported our experience with the off-label use of sorafenib in Chinese cancer patients. A total of 8 patients (7 with papillary and 1 with follicular thyroid cancer) were recruited in this study. The partial response (PR) rate was 50.0% and 5 of the 8 patients (62.5%) achieved a durable response. The median progression-free survival (PFS) and overall survival (OS) were 40.1 and 55.0 weeks, respectively. Lung metastases were more sensitive to sorafenib compared to lymph nodes. The tumor marker response was not in accordance with the radiological response, although patients with tumor marker complete response (CR) exhibited a longer PFS and OS compared to those without a CR. Common adverse events (AEs) included palmar-plantar erythrodysesthesia, hypertension, diarrhea, weight loss and alopecia. Grade 4 AEs comprised hypocalcemia (1 patient) and elevated amylase levels (1 patient). A dose reduction was required in 62.5% of the patients. In conclusion, sorafenib exhibited a clinically relevant antitumor activity in patients with progressive metastatic RAI-refractory DTC, although the majority of the patients required a dose reduction due to intolerable toxicity.

Prognostic Value of Early Postoperative Tumor Marker Response in Gastric Cancer

The clinical usefulness of tumor markers as predictors of treatment outcome in patients with stomach cancer after radical gastrectomy has been poorly defined. The purpose of this study was to evaluate a comprehensive understanding of the impact of early postoperative tumor marker normalization on survival after gastrectomy. Between January 2001 and December 2007, we enrolled 206 patients who had received radical gastrectomy as an initial treatment and had elevated carcinoembryonic antigen (CEA) (>5 ng/mL) or carbohydrate antigen (CA) 19-9 (>37 U/mL) levels. Early tumor marker response was defined as a normalization of preoperative CEA or CA19-9 values 1-2 months after gastrectomy. The mean patient age was 61 years (range 29-84 years), and 139 patients (67.5%) were male. Early tumor marker response was identified in 150 of 206 (72.8%) patients. Of the patients, 49 (23.8%), 41 (19.9%), and 116 (56.4%) were stages I, II, and III, respectively, according to the seventh edition of the American Joint Commission on Cancer (AJCC) staging system. Both disease-free survival (DFS) and overall survival (OS) were significantly longer in patients with tumor marker response compared with nonresponse (61.5 vs. 37.6 months; P = 0.010 and 71.3 vs. 50.9 months; P = 0.008, respectively). Multivariate analyses showed that high CA19-9 level, early tumor marker response, and tumor, node, metastasis classification system stage were independent predictors of DFS and OS (P < 0.05). Early CEA or CA19-9 normalization after radical gastrectomy is a strong prognostic factor for gastric cancer, especially in patients with high preoperative levels of tumor markers.

Massively parallel sequencing (MPS) of circulating DNA in patients with metastatic colorectal cancer (mCRC): Prognostic significance and early changes during chemotherapy (CT).

11015 Background: Prognostic and predictive biomarkers in mCRC are urgently needed. Circulating tumor cells are a promising blood biomarker, but are detectable in only a minority of pts. Recently, analysis of circulating tumor DNA (ctDNA) has shown promise as a liquid biopsy, reflecting the evolving mutational status of the tumor. Here we explored baseline ctDNA as a prognostic marker, and early changes in ctDNA as a marker of CT response. Methods: Serial plasma samples and CEA were collected at baseline (D1), day 3 (D3) and cycle 2 day 1 (C2D1) from 40 mCRC pts receiving standard combination CT. Restaging scans performed at 8 weeks were centrally assessed using RECIST criteria. Samples were analyzed at Johns Hopkins Kimmel Cancer Center. Initially tumor tissue was analyzed for hotspot mutations in TP53, APC, KRAS, BRAF, PIK3CA and FBXW7. The same mutation was queried and quantified in plasma using a MPS platform (Safe-SeqS). Log-rank test was used to compare survival curves and Wilcoxon matched pairs test was used to compare paired plasma samples. Results: Preliminary data is available on 19 pts in this ongoing study. Using our initial panel at least 1 mutation was found in 16 of 19 (84.2%) tumors (7 KRAS, 3 TP53, 3 BRAF, 2 APC and 1 PIK3CA), with matching ctDNA found for each pt. For the remaining 3 cases a further panel of mutations is being analyzed. Median D1 cell free DNA (cfDNA) and ctDNA levels were 1.98 ng/ul (0.15 – 57.18) and 523 mutant fragments (frag)/ml (0.4 – 109,876), respectively. Pts with D1 cfDNA of ≥ 2.5 compared with &lt; 2.5 had shorter median overall survival (OS; 6.9 v 12.2 months, p = 0.0086), with a trend for shorter progression-free survival (PFS; 3.6 v 8.2 months, p = 0.3477). A surge of ctDNA level from D1 to D3 was typically observed (median increase: 91.2 frag/ml, p = 0.0313), followed by a drop (median decrease from D1 to C2D1: 208.8 frag/ml, p = 0.0098). All pts with a decrease in ctDNA at C2D1 had a reduction in tumor size at 8 weeks. Conclusions: In all cases of mCRC where tumor mutation was identified, matching ctDNA was detected in plasma. Circulating DNA is a promising marker of prognosis. Early changes in DNA levels may be a useful marker of tumor response.

A phase I imaging and pharmacodynamic trial of CS-1008 in patients (pts) with metastatic colorectal cancer (mCRC).

2583 Background: Death receptor 5 (DR5) is a member of the TNFR superfamily that initiates the extrinsic apoptotic pathway. CS-1008 is a humanised, monoclonal IgG1 agonistic antibody (Ab) to human DR5 created by CDR grafting of the murine Ab TRA-8. The aim of this study was to investigate the impact of CS-1008 dose on biodistribution, quantitative tumor uptake and anti-tumor response in pts with mCRC. Methods: Pts with mCRC were treated with weekly IV CS-1008 in 5 non-sequential cohorts (Co). Different loading doses were used on days 1 and 8 (0.2 to 6 mg/kg), followed by a weekly dose of 2 mg/kg. D1 and D36 doses were trace-labeled with 111In, followed by whole-body planar and regional SPECT imaging over 10 days. Primary endpoints: initial biodistribution, pharmacokinetic (PK) and tumor uptake following single infusion; changes in biodistribution, PK and tumor uptake following sequential doses. Secondary endpoints: tumor response; changes in tumor metabolism by FDG-PET; serum apoptosis biomarkers and tumor response markers. Results: 19 pts (median age 64 yrs; M:F 11:8; 2-6 prior chemotherapy regimens) were enrolled as follows: Co 1, n=2; Co 2, n=4; Co 3, n=5; Co 4, n=3; and Co 5, n=5. Tumor uptake was variable: 7 pts had no uptake, 11 pts had uptake in all sites of disease but liver, 1 pt showed liver uptake. Tumor uptake and PK were not affected by dose or repeated drug administration. No anti-CS-1008 Ab responses were detected. DR5 expression in archived samples did not correlate with uptake or response. 111In‐CS‐1008 biodistribution showed gradual blood pool clearance and no abnormal uptake in normal tissue. Mean % change in SUVmax from baseline in lesions with uptake was higher than in those with no uptake. There were 8 SD, 1 PR and 10 PD. Duration of PR was 3.7 months (mo). Mean duration of SD was 4 mo. Disease control rate (SD + PR) in pts with uptake was 58% vs 28% of pts with no uptake. Lesions with no uptake were more likely to progress, with a PD risk of 3.4 times higher than those lesions with uptake. Conclusions: Tumor DR5 expression, assessed by 111In-CS-1008 imaging, revealed real-time heterogeneous DR5 expression and appeared to be a promising predictive imaging biomarker of clinical benefit in pts with mCRC receiving CS-1008. Clinical trial information: NCT01220999.

Phase I/II trial of intraperitoneal implantation of agarose-agarose macrobeads (MB) containing mouse renal adenocarcinoma cells (RENCA) in patients (pts) with advanced colorectal cancer (CRC).

e14517 Background: RENCA tumor cells encapsulated in two concentric agarose layers which release signals to treat advanced cancers is a novel concept that has been substantiated in in vitro and in vivo models as reported in Cancer Research 71(3), 716-735, 2011.We report results of a phase I/II study in advanced CRC pts. Methods: Previously-treated advanced CRC pts (ECOG PS 0-2) were enrolled with informed consent obtained. Pts had intraperitoneal implantation up to 4 times via laparoscopy with 8 (37/40 pts- established dose) or 16 (3/40 pts) RENCA MB/kg. Serial exams, lab profiles, and imaging were done pre- and 3 months (mo.) post-implant to assess efficacy. Endpoints of safety, tumor marker decrease, response, and overall survival (OS) were evaluated. Results: 40 pts were implanted with RENCA MB (12 pts phase I; 28 pts phase II); 17M: 23F. Mean age 58.3. 14/40 pts had &gt;1 implant (≥2: 14 pts; ≥3: 2 pts; =4: 2 pts). Response to MB is marked by a prominent initial rise in CRP, ESR, and IL-6, indicating a systemic inflammatory response (SIR) (100% of pts) and a parallel decrease in CEA and/or CA 19-9 in approximately 70%. SIR including its accompanying fatigue and anorexia lasts days to 3 wks. Overall, there was a statistically significant difference (p=0.009) in OS between the 70% of pts showing a decrease in tumor markers by at least 20% during the first 30 days post-implant (OS; 9.7 mo., C.I. 6.5-13.5) and those who did not (OS; 4.4 mo., C.I. 1.1-7.6). On PET-CT imaging, a striking feature of response, most often seen in pts with the longest OS, is tumor necrosis. MB were well-tolerated and no Grade ≥3 adverse events were treatment-related. Conclusions: For advanced, treatment-resistant CRC pts, early response to MB implantation characterized by tumor marker decrease in association with SIR correlates with a statistically significant increase in OS. RENCA MB represent a possible new therapeutic option for late-stage CRC. Clinical trial information: NCT01053013.

Update on pilot study on antitumor efficacy of intravenously applied synergistic combinations of diflunisal, PAS, and aspirin in patients with advanced solid tumors.

e22114 Background: Due to chronic hypoxia cancer cells are growing in a more acidic environment compared to physiological tissue. Recent preclinical in vitro and in vivo data have shown direct pH-sensitive anti-tumor activity by pore formation and apoptosis when synergistically acting combinations of Diflunisal, Paraaminosalicylic acid (PAS) and Aspirin were applied. Therefore, a pilot study was performed to evaluate its clinical relevance and its update is presented. Methods: A total of 65 patients (n=65) with advanced solid tumors and the lack of standard treatments were treated with a protocol consisting of 3-5 weeks with 2 daily i.v. infusions of Diflunisal and Aspirin for 4 days per week after they had signed an informed consent form. Response evaluation was assessed by PET/CT differentiating in metabolic and metric (RECIST) response and tumor marker where available. Results: Out of 65 patients treated 8 patients suffered from colorectal cancer, 17 from breast cancer, 6 from ovarian cancer, 3 from lung cancer, 3 from gastric cancer, 3 from glioblastoma, 3 from CUP, 1 from hemangioendothelioma, 1 from pleuramesothelioma, 1 from non-Hodgkin lymphoma, 2 from pancreatic cancer, 1 from choledochus cancer, 3 from prostate cancer, 5 from sarcomas, 2 from head and neck cancer, 1 from melanoma, 1 from cervical cancer, and 1 from thyroid cancer, respectively. Side effects related to the therapy have been fatigue grade I (30%), nausea grade I (13,3%), tinnitus (25%), hypertension (2,5%), dyspnea (3,3%) and burning sensation in tumor areas (65%). 33 patients were evaluable for metric response, 20 for metabolic and 19 for tumor marker response assessment. For tumor marker follow up 11 % had a CR, 53 % a PR, 26 % a SD of &gt; 3 month and 11 % a PD. For metric follow up 3 % had a CR, 33 % a PR, 39 % a SD of &gt; 3 month and 24 % a PD. For metabolic follow up 10 % had a CR, 35 % a PR, 35 % a SD of &gt; 3 month and 20 % a PD. Conclusions: This continuing pilot study confirms a direct pH-sensitive synergistic anti-tumor activity of intravenous Diflunisal, PAS and Aspirin in patients with advanced solid tumors. Therefore, a further evaluation in a controlled clinical phase II study should be performed.

Tu1085 Mantle Cell Lymphoma With Gastrointestinal Involvement: Characteristics and Clinical Outcome

Objective: Helicobacter pylori eradication has widely accepted as a primary treatment for gastric marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT). We evaluated long-term clinical outcome of low-grade gastric MALT lymphoma in a single center. Methods: From 1996 to 2010, a total of 205 H. pylori-infected patients with lowgrade gastric MALT lymphoma were prospectively enrolled in Seoul National University Hospital. Twelve patients were excluded due to presence of extra-gastric MALT lymphoma or other malignancy at initial diagnosis. Complete remission (CR) was defined as no endoscopic findings of lymphoma, and histopathology of complete histological response (ChR) or probable minimal residual disease (pMRD). Tumor response to H. pylori eradication therapy was evaluated by endoscopy and histopathology every 2-3 months till CR and every 6-12 months after achieving CR. Results: Median follow-up period was 5.4 years (range, 1.0-14.4 years). H. pylori was successfully eradicated in 187 (96.9%) of 193 eligible patients. CR was obtained in 170 (88.1%) patients and the median time to achieve CR was 3 months (range, 1-20 months) after H. pylori eradication therapy. Tumor recurrence was found in 7 (4.1%) patients and the median tumor recurrence time was 13 months (range, 3-61 months) after achieving CR. Cumulative recurrence rate was 1.9, 4.2 and 7.8% at 1, 3 and 5 years, respectively. Disease-free survival was 97.0, 96.1 and 94.8% at 3, 5 and 7 years, respectively. Other malignancies were found in 8 (4.1%) of 193 patients, none of whom had metachronous gastric cancer. Five-year and 10-year overall survival rate was 99.4 and 97.4%, respectively. Tumors of the proximal stomach (mid-body to fundus) (odds ratio [OR] 4.39, 95% confidence interval [CI] 1.34-14.43; p=0.015) and low serum total cholesterol level (,170 mg/dL) (OR 4.17, 95% CI 1.27-13.71; p=0.019) increased the risk of non-CR after H. pylori eradication therapy. Conclusions: Most patients with low-grade gastric MALT lymphoma treated by H. pylori eradication therapy showed excellent long-term outcomes. Serum total cholesterol might be a novel predictive marker for tumor response to H. pylori eradication therapy.

Tu1086 Management Strategy for Small Duodenal Carcinoid Tumors: Does Conservative Management With Close Follow-up Represent an Alternative to Endoscopic Treatment?

Objective: Helicobacter pylori eradication has widely accepted as a primary treatment for gastric marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT). We evaluated long-term clinical outcome of low-grade gastric MALT lymphoma in a single center. Methods: From 1996 to 2010, a total of 205 H. pylori-infected patients with lowgrade gastric MALT lymphoma were prospectively enrolled in Seoul National University Hospital. Twelve patients were excluded due to presence of extra-gastric MALT lymphoma or other malignancy at initial diagnosis. Complete remission (CR) was defined as no endoscopic findings of lymphoma, and histopathology of complete histological response (ChR) or probable minimal residual disease (pMRD). Tumor response to H. pylori eradication therapy was evaluated by endoscopy and histopathology every 2-3 months till CR and every 6-12 months after achieving CR. Results: Median follow-up period was 5.4 years (range, 1.0-14.4 years). H. pylori was successfully eradicated in 187 (96.9%) of 193 eligible patients. CR was obtained in 170 (88.1%) patients and the median time to achieve CR was 3 months (range, 1-20 months) after H. pylori eradication therapy. Tumor recurrence was found in 7 (4.1%) patients and the median tumor recurrence time was 13 months (range, 3-61 months) after achieving CR. Cumulative recurrence rate was 1.9, 4.2 and 7.8% at 1, 3 and 5 years, respectively. Disease-free survival was 97.0, 96.1 and 94.8% at 3, 5 and 7 years, respectively. Other malignancies were found in 8 (4.1%) of 193 patients, none of whom had metachronous gastric cancer. Five-year and 10-year overall survival rate was 99.4 and 97.4%, respectively. Tumors of the proximal stomach (mid-body to fundus) (odds ratio [OR] 4.39, 95% confidence interval [CI] 1.34-14.43; p=0.015) and low serum total cholesterol level (,170 mg/dL) (OR 4.17, 95% CI 1.27-13.71; p=0.019) increased the risk of non-CR after H. pylori eradication therapy. Conclusions: Most patients with low-grade gastric MALT lymphoma treated by H. pylori eradication therapy showed excellent long-term outcomes. Serum total cholesterol might be a novel predictive marker for tumor response to H. pylori eradication therapy.

Tu1084 Long-Term Outcome of Low-Grade Gastric Mucosa-Associated Lymphoid Tissue Lymphoma After Helicobacter pylori Eradication Therapy: A Prospective Single Center Study

Objective: Helicobacter pylori eradication has widely accepted as a primary treatment for gastric marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT). We evaluated long-term clinical outcome of low-grade gastric MALT lymphoma in a single center. Methods: From 1996 to 2010, a total of 205 H. pylori-infected patients with lowgrade gastric MALT lymphoma were prospectively enrolled in Seoul National University Hospital. Twelve patients were excluded due to presence of extra-gastric MALT lymphoma or other malignancy at initial diagnosis. Complete remission (CR) was defined as no endoscopic findings of lymphoma, and histopathology of complete histological response (ChR) or probable minimal residual disease (pMRD). Tumor response to H. pylori eradication therapy was evaluated by endoscopy and histopathology every 2-3 months till CR and every 6-12 months after achieving CR. Results: Median follow-up period was 5.4 years (range, 1.0-14.4 years). H. pylori was successfully eradicated in 187 (96.9%) of 193 eligible patients. CR was obtained in 170 (88.1%) patients and the median time to achieve CR was 3 months (range, 1-20 months) after H. pylori eradication therapy. Tumor recurrence was found in 7 (4.1%) patients and the median tumor recurrence time was 13 months (range, 3-61 months) after achieving CR. Cumulative recurrence rate was 1.9, 4.2 and 7.8% at 1, 3 and 5 years, respectively. Disease-free survival was 97.0, 96.1 and 94.8% at 3, 5 and 7 years, respectively. Other malignancies were found in 8 (4.1%) of 193 patients, none of whom had metachronous gastric cancer. Five-year and 10-year overall survival rate was 99.4 and 97.4%, respectively. Tumors of the proximal stomach (mid-body to fundus) (odds ratio [OR] 4.39, 95% confidence interval [CI] 1.34-14.43; p=0.015) and low serum total cholesterol level (,170 mg/dL) (OR 4.17, 95% CI 1.27-13.71; p=0.019) increased the risk of non-CR after H. pylori eradication therapy. Conclusions: Most patients with low-grade gastric MALT lymphoma treated by H. pylori eradication therapy showed excellent long-term outcomes. Serum total cholesterol might be a novel predictive marker for tumor response to H. pylori eradication therapy.

Abstract 5584: Finding predictive markers for tumor response to classical cytotoxic drugs.

Abstract As attempts to find predictive markers for cytotoxic drugs have been relatively unsuccessful using patient tumor samples (1), we are using a mouse model for BRCA1-deficient mammary tumors to search for such markers. Although these tumors originate in inbred mice from an inactivating deletion of the Brca1 and p53 genes, their response to doxorubicin (2), docetaxel (2), topotecan (3) and PARP inhibitors (4) varies. We have shown that in this tumor model 5 of the 22 tumors respond poorly to docetaxel, because of upregulated drug-transporting P-glycoproteins (5). These 5 were not found by standard gene expression analytical tools, such as significance analysis of microarrays (SAM), and we have shown that SAM only detects resistance markers if present in more than half the tumor samples (5). Better algorithms for the detection of resistance determinants in a subfraction of tumors are being developed by De Ronde and Wessels (5). We are still searching for the cause of the poor docetaxel response in 17 of the 22 tumors. 1. Borst,P. and Wessels,L. (2010). Do predictive signatures really predict response to cancer chemotherapy? Cell Cycle 9, 4836-4840. 2. Rottenberg,S., et al (2007). Selective induction of chemotherapy resistance of mammary tumors in a conditional mouse model for hereditary breast cancer. Proc. Natl. Acad. Sci. U. S. A. 104, 12117-12122. 3. Zander,S., et al (2010). Sensitivity and acquired resistance of BRCA1; -53-deficient mouse mammary tumors to the topoisomerase I inhibitor topotecan. Cancer Res. 70, 1700-1710. 4. Rottenberg,S., et al (2008). High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc. Natl Acad. Sci. U. S. A 105, 17079-17084. 5. Rottenberg,S., et al (2012). Impact of intertumoral heterogeneity on predicting chemotherapy response of BRCA1-deficient mammary tumors. Cancer Res 72, 2350-2361. Citation Format: Piet Borst, Sven Rottenberg. Finding predictive markers for tumor response to classical cytotoxic drugs. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5584. doi:10.1158/1538-7445.AM2013-5584

Abstract 1174: A phase I imaging and pharmacodynamic trial of CS-1008 in patients (pts) with metastatic colorectal cancer (mCRC).

Abstract Background: Death receptor 5 (DR5) is a member of the TNFR superfamily that initiates the extrinsic apoptotic pathway by activating caspases. CS-1008 is a humanised, monoclonal IgG1 agonistic antibody to human DR5 created by CDR grafting of the murine antibody TRA-8. The aim of this study was to investigate the impact of CS-1008 dose on biodistribution, quantitative tumor uptake and anti-tumor response in patients with mCRC. Methods: Pts with mCRC who had received at least 1 course of chemotherapy (CT) were treated with weekly IV CS-1008 infusions in 5 non-sequential cohorts (Co). Different loading doses were used on days 1 and 8 (Co 1: 0.2 and 6 mg/kg; Co 2: 1 and 6 mg/kg; Co 3: 2 and 6 mg/kg; Co 4: 4 and 4mg/kg; Co 5: 6 and 2 mg/kg), followed by a weekly CS-1008 dose of 2 mg/kg. Cycle 1 encompassed 7 wks of therapy (D1 and D36 doses trace-labeled with 111In); additional weekly CS-1008 was scheduled as 4-wk cycles. Primary endpoints were to determine (1) the influence of CS-1008 dose on initial biodistribution, pharmacokinetic (PK) and tumor uptake of 111In-CS-1008 following single infusion; (2) changes in biodistribution, PK and tumor uptake following sequential doses. Secondary endpoints were to determine (1) anti-tumor response; (2) changes in tumor metabolism; (3) serum apoptosis biomarkers and serum tumor response markers. Results: Nineteen pts with a median age of 64 years and 2-6 prior CT lines were enrolled as follows: Co 1, 2 pts; Co 2, 4 pts; Co 3, 5 pts; Co 4, 3 pts; and Co 5, 5 pts. Twelve pts showed tumor uptake of 111In-CS-1008, 3 at each of the 1, 2, 4 and 6 mg/kg D1 dose levels. 111In-CS-1008 uptake in tumor was variable: some pts showed no uptake, in others uptake was observed in all measurable lesions. Liver metastases showed poor uptake of CS-1008. No significant differences were observed in tumor uptake between D1 and D36, and no effect of dose on tumor uptake was seen. DR5 expression in archived samples did not correlate with 111In-CS-1008 uptake, nor with clinical outcome. 111In-CS-1008 biodistribution showed gradual blood pool clearance and no discernible abnormal uptake in normal tissue. CS-1008 PK was not affected by dose or repeated drug administration. At restaging, there were 8 SD, 1 PR and 10 PD. The duration of PR was 3.7 months (mos). The mean duration of SD was 4 mos (range, 2.6-6.7 mos). Among the group of pts who showed CS-1008 uptake in tumor, 58% had clinical benefit (SD or PR), compared with 28% of pts in the group with no tumor uptake. The lesions that showed CS-1008 uptake were less likely to progress even in pts with overall PD at restaging. Conclusions: 111In-CS-1008 uptake in tumor predicts SD or PR. Tumor DR5 expression, assessed by 111In-CS-1008 imaging, reveals real-time heterogeneous DR5 expression, both on a per pt and on a lesion by lesion basis, and appears to be a promising predictive imaging biomarker of clinical benefit in pts with mCRC receiving CS-1008. Citation Format: Marika Ciprotti, Niall C. Tebbutt, Fook T. Lee, Sze T. Lee, Dave C. McKee, Graeme J. O'Keefe, Sylvia J. Gong, Geoffrey Chong, Hui K. Gan, Wendie Hopkins, Bridget Chappell, Nancy Y. Guo, Fiona E. Smyth, Archie N. Tse, Mendel Jansen, Manabu Matsumura, Rira Watanabe, Robert A. Beckman, Jon Greenberg, Andrew M. Scott. A phase I imaging and pharmacodynamic trial of CS-1008 in patients (pts) with metastatic colorectal cancer (mCRC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1174. doi:10.1158/1538-7445.AM2013-1174

Advanced Hepatocellular Carcinoma: Early evaluation of response to targeted therapy and prognostic value of Perfusion CT and Dynamic Contrast Enhanced-Ultrasound. Preliminary results

PurposeTo investigate whether there is any correlation between standard endpoints and tumor perfusion measurements with Perfusion CT and Dynamic Contrast-Enhanced Ultrasonography (DCE-US) in patients with advanced Hepatocellular Carcinoma (HCC) treated with targeted therapy. Materials and methodsNineteen patients were evaluated during targeted therapy (sorafenib n=16, sunitinib n=3). Changes in tumor perfusion measurements between baseline and month 1 were assessed and compared using RECIST progression criteria at month 2. ResultsMedian time to progression according to RECIST was 117 days and median time to death was 208 days. Perfusion CT values before treatment were significantly increased in HCC compared to the surrounding liver (n=17, P<.02). Eleven patients received complete examinations with both techniques at baseline and month 1. A non-significant decrease was found in all Perfusion CT values between RECIST nonprogressors (n=7) and progressors (n=4): mean Blood Volume: −27.9 vs. −11.1% and mean Blood Flow: −25.0 vs. −11.7% respectively. With DCE-US, opposite changes were found (mean Area Under the Curve AUC: −38.3 vs. 436.3%). RECIST progression at month 2 was significantly correlated with a threshold 40% decrease in AUC (P=.015). None of the patients with a decrease in AUC≥40% was a progressor at month 2. ConclusionDespite perfusion changes with both Perfusion CT and DCE-US in patients receiving treatment, only DCE-US at month 1 (with a decrease in the AUC of more than 40%) predicted non-progression at month 2 and may be a potential surrogate marker of tumor response during targeted therapy.

Abstract P4-02-07: Early Optical Tomography Changes Predict Breast Cancer Response to Neoadjuvant Chemotherapy

Abstract Background: Pathologic complete response (pCR) or a low Residual Cancer Burden (RCB) score following neoadjuvant chemotherapy (NACT) predicts a superior survival in breast cancer (BC) patients. An early predictive marker of tumor response during NACT would provide a way to optimize treatment for non-responders; however, no ideal technology currently exists. Diffuse optical tomography (DOT) is a novel, fast, safe, and low-cost technique that uses near infrared light to provide 3D data on tissue vascularity without the use of radiation, making it a promising technology for assessing early tumor response to NACT. We hypothesized that a 2-week change in DOT parameters would predict response to NACT as measured by the RCB score. Methods: Women with stage II-IIIc invasive BC scheduled to undergo NACT with 12 cycles of a weekly taxane followed by 4 cycles of doxorubicin with cyclophosphamide (AC) were enrolled. Treatment with additional biologic therapies was allowed. DOT measurements were made before starting NACT, 2 weeks into treatment, and before surgery. Concentrations of oxyhemoglobin [HbO2], deoxyhemoglobin [Hb], total hemoglobin [HbT], and tissue scattering (SC) were measured by DOT. Final pathology specimens were scored for the RCB index (continuous measure), RCB class (0, 1, 2, 3), and a dichotomized RCB score (RCB class 0 or 1: responders to NACT; RCB class 2 or 3: non-responders). Correlation analysis, ANOVA testing, and two sample t-tests were used to evaluate the relationship between the two-week changes in DOT parameters and the RCB score. Results: Since July 2011, we have recruited 11 pts, of whom 7 have undergone surgery. Complete data is available for 6 pts. Two of 7 pts had a pCR (RCB 0), 1 had RCB 1, 3 had RCB 2, and 1 had RCB 3. The Pearson correlation between the 2-week change in [Hb] and the continuous RCB index was 0.94 (p = 0.0047), and that between the 2-week change in SC and the RCB index was 0.93 (p = 0.0073). At 2 weeks, the [Hb] decreased by 6.7% for pts whose pathology demonstrated an RCB 0 (pCR), 1.8% for RCB 1, 0.6% for RCB 2, and increased 0.7% for RCB 3. ANOVA and Tukey testing demonstrated a significant difference in the [Hb] change for pts with RCB 0 compared to pts with RCB 1, 2, or 3 (p &amp;lt;0.05). At 2 weeks, SC decreased by 26.5% for pts with RCB 0, 19.3% for RCB 1, 3.7% for RCB 2, and increased by 25.1% for RCB 3. There was a significant difference in the SC change for pts with RCB 0 compared to pts with RCB 3 (p &amp;lt;0.05). Responders (RCB 0/1) had a 5% decrease in [Hb] at 2 weeks compared to non-responders (RCB 2/3) who had a decrease in 0.18% in [Hb] (p = 0.0045), and responders had a 24% decrease in SC compared to non-responders who had an increase in 6% (p = 0.044). Conclusions: DOT change is an early predictor of response to NACT as measured by the RCB score. We found a significant linear association between the RCB index and the 2-week change in [Hb] and SC. Significantly different changes in DOT parameters were associated with the other RCB classifications. Additional recruitment is ongoing and differences by tumor subtype will be evaluated. *These two authors contributed equally to this study Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-02-07.

833P - Dynamic Changes in Plasma Osteopontin as a Markers of Tumor Response in Metastatic Renal Cell Carcinoma (RCC) Patients Treated with Pazopanib

ABSTRACT Background In a Phase II RCC study of pazopanib (VEG102616) a response rate of 34.7% and disease control rate (CR + PR +SD) of 80% were observed (Hutson, JCO 2009. Previously, we reported that elevated levels of E-Selectin, lower levels of IL-6 and HGF were correlated with longer PFS and decrease in tumor shrinkage. Higher levels of IL-6 and IL-8 correlated with greater tumor burden (Tran ASCO 2010). IL-8, OPN, HGF and TIMP1 correlated with PFS and IL-6, IL-8 and OPN were prognostic markers (Yuan GU ASCO 2011, Tran ESMO 2011). In this study, we measured CAF levels at baseline, week 4 and week 12 after inititation of pazopanib therapy and evaluated for dynamic changes in CAF as potential marker for tumor response and clinical benefits Methods Six candidate CAFs (TIMP1, IL-6, IL-8, HGF, E-Selectin, and OPN) were measured in 173 patients (pts) whose plasma samples were collected during the treatment at week 4, and week 12 by using Searchlight Protein Array (Aushon). CAF levels at each time point and changes of CAF levels from baseline at week 4 and week 12 were correlated with maximum tumor shrinkage (MTS) by linear regression; PFS by Cox regression; baseline tumor burden using baseline sum of longest tumor diameter and best response by Spearman. Results Decreases in OPN levels from baseline at week 4 (p = 0.030) and week 12 (p = 0.006) show significant correlations with MTS. At week 4, changes in E-Selectin from baseline was trending (p = 0.053) in correlation with MTS. With PFS, changes in IL-6 level from baseline at week 12 has near significant correlation with PFS (p = 0.05). E-Selectin has an inverse baseline to week 4 significant correlation with best response status week 4 (p = 0.0245) but not at week 12. Conclusion Decreasing levels of osteopontin from baseline at week 4 and 12 correlated with improved tumor shrinkage; while increase in IL-6 portends shorter PFS and E-Selectin was inversely correlated with best response status. Additional investigation is needed to evaluate the dynamic changes of CAFs as an approach to monitor patients while on pazopanib therapy as marker of tumor response. Disclosure Y. Liu: Stock ownership: Yes; GSK Membership on an advisory board or board of directors: No Corporate-sponsored research: No Other substantive relationships: No A. Martin: Stock ownership: Yes; GSK Membership on an advisory board or board of directors: No Corporate-sponsored research: No Other substantive relationships: No K.L. Baker-Neblett: Stock ownership: Yes; GSK Membership on an advisory board or board of directors: No Corporate-sponsored research: No Other substantive relationships: No. L.N. Pandite: Stock ownership: Yes; GSK Membership on an advisory board or board of directors: No Corporate-sponsored research: No Other substantive relationships: No. J.V. Heymach: Stock ownership: No Membership on an advisory board or board of directors: Yes; GSK Corporate-sponsored research: Yes; GSK for biomarker analysis. Other substantive relationships: No. All other authors have declared no conflicts of interest.